A phase II Study of fedratinib and nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment – fraction Study / IKF051 / gsg-MPN-006

Abstract

Abstract Introduction: Early clinical trials for patients with myelofibrosis (MF) are aimed to improve treatment using combinatorial therapies for patients with suboptimal response to Ruxolitinib therapy. Trials investigating combination therapies with Fedratinib are scarce. Fedratinib is JAK2 specific and permissive for immune functions. Recent reports provided first evidence on how JAK2 mutations in myeloid cells may affect T-cell responses through upregulation of PD-L1, thus facilitating the use of immunotherapeutic approaches in MPN. Immune checkpoint inhibitor monotherapy had shown rather modest responses in MPN due to short exposure times and insufficient symptom control. Here, Nivolumab, an established checkpoint-inhibitor with an excellent safety profile was studied as combinatorial therapy with Fedratinib. Study Design: FRACTION is a single arm, open label Phase II trial investigating the combination of Fedratinib with the PD-1 inhibitor Nivolumab in patients with MF and suboptimal (e.g. anemia, splenomegaly or persitence of symptoms) or lack of response to JAK-inhibitor therapy. The primary efficacy endpoint of the study assessed the best response rate within 12 treatment cycles according to the IWG-MRT criteria. Secondary endpoints include the overall safety profile as well as the cumulative incidence of leukemic transformation, clinical benefit, progression-free survival (PFS), duration of response, overall survival (OS) and reduction of disease burden. Fedratinib was started at 400mg QD. Nivolumab was added from cycle 2 on every 2 weeks at a fixed dose of 240mg i.v. Results: At time of data cut-off, of 30 patients, 12 had completed at least 9 cycles of therapy and 9 had completed 12 cycles. Median age was 66.5 years. ≥ 2 mutations were present in 13 (43.3%) pts. Median time from diagnosis to treatment was 64.1 mo. Currently, 6 pts (20%) remain on treatment, the median treatment duration was 12.6 mo. The most common reasons for discontinuing the combinatorial treatment include lack of response (n = 3), disease progression (n = 5), patient decision (n = 2) immune-toxicity (n = 2) and patient death (n = 5). A clinical benefit rate of 23.3% was observed, including patients who achieved improvement in anemia and/or symptom burden as assessed by MPN-SAF scores. 18 (60%) pts were transfusion independent at end of treatment. Among 23 pts with palpable splenomegaly treated for ≥ 24 weeks, spleen was no longer palpable in 4 patients (13.3%); 3 pts who were treated for ≥ 24 weeks had symptomatic disease at baseline. Regarding molecular responses, 13 (43.3%) patients showed partial molecular responses (as indicated by 50% reduction in VAF). The primary endpoint including overall response rate (CR, PR, SD and CI) will be analyzed with the last patient having concluded 12 cycles in 10/2025 and will be reported at the conference. With a median follow-up of 12.6 months, median OS is estimated at 25.6 months. 30 pts were evaluable for safety. Treatment-emergent AEs occurring in 90% of pts were Nausea (30%), Anemia (20%), Fatigue (16.7%), Alanine aminotransferase increased (13.3%), and creatinine increase (13.3%). The vast majority of TEAEs were grade 1 or 2 (Nausea and Fatigue). Grade 3/4 thrombocytopenia occurred in 6.7% of patients and resolved with dose reduction in 3.3% of patients. Immune-related toxicities did not exceed the expected rates of nivolumab monotherapy in the literature. Conclusion: Fedratinib-Nivolumab combination demonstrates promising clinical efficacy in a cohort of MF pts enriched for int-2 or high-risk, especially in those with proliferative features indicated by leukocytosis and thrombocytosis and was well tolerated leading to prolonged treatment durations. The safety profile is consistent with prior experience. Fedratinib's unique kinase inhibition profile may provide a mechanism for enhanced effectiveness in this pt population.